1. Chapter 21 The Chemistry of Carboxylic Acid Derivatives

2. Carboxylic Acid Derivatives Carboxylic acid derivative: a compound that has an acyl group bonded to an electronegative atom or substituent that can act as a leaving group in a substitution reaction – can be hydrolyzed under acidic of basic conditions to give a carboxylic acid 2

3. Structures of Carboxylic Acid Derivatives 3 21.1 Nomenclature and Classification of Carboxylic Acid Derivatives

4. Reactions of Carboxylic Acid Derivatives Chemistry dominated by nucleophilic acyl substitution rxns: 4

5. Hydrolysis Reactions 1)Hydrolysis of Esters a)Basic Hydrolysis (Saponification) b)Acid Catalyzed Hydrolysis 5

6. Basic Hydrolysis 6

7. Acid Catalyzed Hydrolysis 7

8. 2)Hydrolysis of Amides Happens under both acidic and basic conditions Conditions harsher than those of ester hydrolysis 8 + NH 4 + /NH 2 -

9. Basic Hydrolysis Acidic Hydrolysis 9

10. 3)Hydrolysis of Nitriles Occurs in both acidic and basic environments More extreme conditions are required compared to those of esters and amides 10

11. Basic hydrolysis 11 21.7 Hydrolysis of Carboxylic Acid Derivatives

12. Acidic hydrolysis 12

13. Imidic acids can be viewed as the nitrogen- analogs of enols 13

14. Problem Write out the mechanism for the following rxn: 14

15. Nucleophilic Acyl Substitution Reactions The conditions for hydrolysis for these derivatives can differ considerably 15 21.7 Hydrolysis of Carboxylic Acid Derivatives

16. 16

17. 17

18. Reactions of Acid Chlorides with Amines: Aminolysis 18 21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

19. Conversion of Acid Chlorides into Esters: Alcoholysis 19 21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

20. Reactions of Acid Chlorides with Carboxylate Salts: Preparation of Anydrides 20 21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

21. Problems 1)Give the products for the following rxns: 21

22. 2)Draw the mechanism for the following reaction: 22

23. Reactions of Anhydrides with Nucleophiles 23 21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

24. Reactions of Esters with Nucleophiles Transesterification: 24 21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles

25. Problems Give the products for the following rxns: 25

26. Reduction Carboxylic Acid Derivatives 1)Reduction of Esters LiAlH 4 preferred over NaBH 4 26

27. -78°C, DIBAH = Diisobutyl aluminum hydride 27

28. 2)Reduction of Amides to Amines – Net effect is conversion of C=O to CH 2 28 21.9 Reduction of Carboxylic Acid Derivatives

29. Reduction of Amides to Amines Note how the amide reduction differs from that of ester reduction 29 21.9 Reduction of Carboxylic Acid Derivatives

30. Note that a protonolysis step with aqueous acid follows the LiAlH 4 reduction This is followed by base to free the amine 30

31. 31 21.9 Reduction of Carboxylic Acid Derivatives

32. 32 21.9 Reduction of Carboxylic Acid Derivatives

33. 3)Reduction of Nitriles to Primary Amines 33 21.9 Reduction of Carboxylic Acid Derivatives

34. Two successive nucleophilic additions occur 34

35. Intermediate imine not isolated 35 21.9 Reduction of Carboxylic Acid Derivatives

36. 4)Reduction of Acid Chlorides to Aldehydes – The Rosenmund reduction: – H 2 gas over Pd on C Poisoned with BaSO 4 or quinoline – Keeps aldehyde from further reducing to alcohol 36

37. Derivatives of LiAlH 4 can also be used Can also use DIBAH 37 21.9 Reduction of Carboxylic Acid Derivatives

38. Problems Draw the products for the following rxns: 38

39. 39

40. Reactions of Esters with Grignard Reagents Tertiary alcohol produced Two substituents are identical 40 21.10 Reactions of Carboxylic Acid Derivatives with Organometallic Reagents

41. Reactions of Acid Chlorides Grignard Reagents 41 21.10 Reactions of Carboxylic Acid Derivatives with Organometallic Reagents

42. Reactions of Acid Chlorides with R 2 CuLi R 2 CuLi = Gilman reagent Dialkylcuprates are less reactive than Grignard reagents Allow rxn to stop at ketone Only works with acid chlorides, not with other carboxylic acid derivatives 42

43. Problems Draw the product for the following rxns: 43